2-amino-thieno(2,3-e)(1,4)diazepine compounds

ABSTRACT

2-AMINO-THIENO(2,3-E)(1,4)DIAZEPINE COMPOUNDS OF THE GENERAL FORMULA:   2-(R3-N(-R4)-),5-(X-PHENYL),6-R1,7-R2-THIENO(2,3-E)(1,4)   DIAZEPINE   WHERE X IS H, HALOGEN, METHYL, METHOXY OR TRIFLUOROMETHYL; EACH OF R1 AND R2 IS H OR C1-4 ALKYL, OR R1 AND R2 COMBINEDLY FORM -(CH2)4-; AND -N(R3) (R4) IS AMINO, ALKYL- OR DIALKYL-AMINO (ALKYL BEING C1-4 ALKYL), 1PYRROLIDINYL, PIPERIDINO, MORPHOLINO OR 4-METHYL-1-PIPERAZINYL; AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, ARE USEFUL AS PSYCHOTRIPICS.

United States Patent 3,828,039 2-AM]NO-THIENO[2,3-e][1,4]DIAZEPINE COMPOUNDS Int. Cl. A61k 27/00; C07d 63/12, 63/14 US. Cl. 260247.1 16 Claims ABSTRACT OF THE DISCLOSURE Z-amino-thieno [2,3-e] [1,4] diazepine compounds of the general formula:

This invention relates to novel and therapeutically valuable 2-amino-thieno[2,3-e] [1,41diazepine compounds of the general formula:

and pharmaceutically acceptable acid addition salts thereof, wherein X is H, halogen (e.g. F, C1 or Br), methyl, methoxy or trifiuoromethyl; each of R and R is H or C alkyl such as methyl, ethyl, propyl, butyl or isobutyl, or R and R combinedly form (CH and is amino, alkylor dialkyl-amino (alkyl being C alkyl),

l-pyrrolidinyl, piperidino, morpholino or 4-methyl-1-piperazinyl.

ice

The compounds of general formula (I) can be produced by reacting a compound of the formula with a compound of the formula R8 HN R (III) The reaction is usually carried out in an inert solvent such as ether, tetrahydrofuran or dioxane, in the presence of a Lewis acid such as TiCl BF SnCl ZnCl or AlCl as dehydrating catalyst, at a relatively low temperature (about 10 C. to room temperature) for about 1 to 10 hours. The reaction can also be carried out (1) in an inert solvent such as dimethylformamide, dimethylacetamdie or diglyme, preferablyin a pressure vessel such as an autoclave, at about to 200 C., for about 5 to 10 hours, or (2) in an inert solvent such as benzene, toluene or xylene, in the presence of a catalyst such as p toluenesulfonic acid, under heating, in order to remove continuously the water formed.

The starting compounds of formula (II) can be prepared, for example, by the method disclosed in published West German patent application DIS-2,107,356, namely by subjecting a compound of the formula Q Bl NH O H H 8 C C 2N 1 (In) to intramolecular condensation.

The compounds of formula (I) can be converted into the corresponding acid addition salts in a conventional manner by treatment with various inorganic and organic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric, citric, maleic, fnmaric, succinic, oxalic and tartaric acid.

The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof are excellent in' anticonvulsant action, antimegimide effect, antitremorine action and reserpine potentiation. Some test results are shown below:

(1) ANTICONVULSANT ACTION A test solution containing a test compound was intraperitoneally administered to one group of 6 dd-strain male mice each weighing 20-25 g. After an hour, a silver electrode of an electroshock seizure apparatus (designed by L. A. Woodbury et al.: see, Archives Internationales de Pharmacodynamie et de Therapie, vol. 42,

3 pp. 72-1021:( 1952)) was brought into contact with the eorneaand an alternating current (2000 volts, 12.5 milliamperes) was applied for 0.2 second to induce convulsion. The ED the dose required to lower the seizure rate by 50% against the control mice, was determined from the dose-effect correlation curve.

(2) ANTIMEGIMIDE EFFECT A test solution containing a test compound was orally administered to one group of 6 dd-strain male mice. After minutes, a solution of 80 mg./ lcg. of megimide (,6- ethyl-fl-methyl-glutarimide) was subcutaneously administered. The ED5 the dose required to prevent for 3 hours the death due to the tonic extensor convulsion induced by the administration of megimide in 50% of the test animals, was determined from the dose-effect correlation curve.

(3) ANTITREMORINE ACTION A test solution containing a test compound was subcutaneously administered to one group of 6 dd-strain female mice. After 30 minutes, a solution of 15 mg./ kg. of tremorine hydrochloride was intraperitoneally administered. Twenty minutes later, it was studied whether tremor and salivation were observed or not. The dose which was efiective for half number of mice is represented as ED The ED was determined from the dose-effect correlation curve.

RE S ULTS Compound Action A B C D Antlconvulsant action, ED, mgJkg--- 12 12 7 9. 5 Antimegimide efieet, EDm, mgJkg 3. 7 4. 2 l3 3. 5 Antitremorlne action, EDm, mgJkg 160 8 8. 5

Compounds A to D are identified below:

(A) Z-dimethylamino-5-o-chlorophenyl-7-ethyl-3H- thieno [2,3-e] [1,4]diazepine hydrochloride.

(B) Z-piperidino-S-o-chlorophenyl-7-ethyl-3H-thieno [2,3-e] [1,4] diazepine dihydrochloride.

(C) Z-ethylamino-5-o-chloropheny1-7-ethyl-3H- thieno[2,3-e] 1,4]diazepine oxalate.

(D) 2-methylamino-5-o-chlorophenyl-7-ethyl-3H- thieno [2,3e] 1,4] diazepine hydrochloride.

FORMULATION EXAMPLES (a) 10 mg. tablets are prepared from the following compositions:

Mg. Compound (I) 10 Starch 8.5 Microcrystalline cellulose l0 Lactose n 50 Methyl cellulose 0.5 Magnesium stearate 1 4 (b) 10% powders are prepared from the following compositions:

Percent by weight Compound (I) l0 Lactose Starch 9.5 Methyl cellulose 0.5

EXAMPLE 1 Dry ammonia gas is introduced to a solution of 6.0 g. of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3I-I-thieno[2,3-e] [l,4]diazepin-2-one in 180 m1. of anhydrous tetrahydrofuran, at 5 to 0 C., and 20 minutes later 70 ml. of a tetrahydrofuran solution containing 2.0 g. of TiCL; is added dropwise over a period of 20 minutes. The whole mixture is stirred under the introduction of ammonia gas at 0 to 5 C. for 2 hours, and then, without the ammonia introduction, at room temperature for 2 hours. Then 12 ml. of water is added to the reaction mixture, the aqueous mixture is stirred for 10 minutes, the insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. Ethanol (50 ml.) is added to the residue, the ethanolic solution is heated for a short time, and the crystalline insoluble matter is collected by filtration. The crude crystalline product is recrystallized from a mixture of ethanol and chloroform to give 1.2 g. of Z-amino-S-ochlorophenyl 7 ethyl 3H thieno[2,3-e] [1,4]diazepine as pale yellow crystals, melting at 247248 C.

EXAMPLE 2 6.0 g. of 5-o-chlorophenyl 7 ethyl 1,2 dihydro-SH- thieno[2,3-e][l,4]diazepin-2-one is dissolved in ml. of a tetrahydrofuran solution containing 25 g. of dimethylamine, 80 ml. of a tetrahydrofuran solution containing 2.5 g. of TiCL, is added dropwise over a period of 20 minutes under ice-cooling, and the whole mixture is stirred at room temperature for 6 hours. Then 15 ml. of water is added to the reaction mixture, the aqueous mixture is stirred for 10 minutes, the insoluble matter is removed by suction filtration, and the filtrate is concentrated under reduced pressure. The oily residue is dissolved in ethyl acetate, the organic solution is Washed well with water, and dried over sodium sulfate, the solvent is distilled off under reduced pressure, and then hot ligroin is added to the remaining oil. After cooling the ligroin solution, the precipitated insoluble matter (unreacted starting com pound) is filtered off, and the filtrate is concentrated to give 4.2 g. of Z-dimethylamino-S-o-chlorophenyl-7-ethyl- 3H-thieno[2,3-e][l,4]diazepin as pale yellow oil. This oil is dissolved in ethyl acetate, and an equimolar amount of 30% ethanolic hydrochloric acid is added. The crystals precipitated are collected by filtration, and recrystallized from a mixture of ethyl acetate and ethanol to give the corresponding hydrochloride as yellow powder, melting at 249-250 C. with decomposition.

EXAMPLE 3 6.0 g. of S-o-chlorophenyl 7 ethyl 1,2 dihydro-SH- thieno [2,3-e] [1,4] diazepin-2-one is dissolved in 150 ml. of a tetrahydrofuran solution containing 20 g. of methylamine, 60 ml. of a tetrahydrofuran solution containing 2.0 g. of TiCl, is added dropwise over a period of 20 minutes under ice-cooling, and the whole mixture is stirred at room temperature for 4 hours. Then 60 ml. of hot ethanol is added to the reaction mixture, the ethanolic mixture is stirred for a short time, and the insoluble matter is collected by filtration. This solid is recrystallized from a mixture of ethanol and chloroform to give 5.1 g. of 2-methylamino 5 o chlorophenyl-7-ethyl-3H-thieno- [2,3-e][1,4]diazepine as pale yellow crystals, melting at 216-217 C. The corresponding hydrochloride melts at 232-234 C.

EXAMPLE 4 To a solution of 6.0 g. of 5-o-chlorophenyl-7-ethyl-1,2- dihydro-3H-thieno[2,3-e] [1,4] diazepin-Z-one and g. of piperidine in 120 ml. of tetrahydrofuran is added dropwise ml. of a tetrahydrofuran solution containing 2.5 g. of TiCl; under ice-cooling for a period of 20 minutes, and the whole mixture is stirred at room temperature for 2 hours. Then 10 ml. of water is added to the reaction mixture, the aqueous mixture is stirred for 10 minutes, the insoluble matter is removed by suction filtration, and the filtrate is concentrated under reduced pressure. The remaining oil is dissolved in ethyl acetate, the organic solution is washed well in order to remove the excess piperidine, and dried over sodium sulfate, and the solvent is distilled off under reduced pressure. Thus is obtained 7.0 g. of almost pure 2 piperidino-S-o-chlorophenyl-7-ethyl- 3H-thieno[2,3-e][1,4]diazepine as red oil. This product is converted into the corresponding hydrochloride by treat ment with an excess ethanolic hydrochloric acid, and the crude salt thus obtained is recrystallized from a mixture of ethyl acetate and ethanol to give the dihydrochloride as yellow crystalline powder. This product damps at 96-l20 C. with foaming due to thermal elimination of one mole of hydrogen chloride under formation of the monohydrochloride, which melts transparently at l192 C.

Using the procedure set forth in the above examples, but substituting equivalent amounts of the appropriate starting materials, the following compounds are also produced: 35

6 What is claimed is: 1. A 2-amino-thieno[2,3-e] [1,41diazepine compound of the general formula:

wherein X is H, halogen, methyl, methoxy or trifluoromethyl; each of R or R is H or C alkyl, or R and R combined form (CH and N(R (R is amino, alkylor dialkyl-amino (alkyl being C alkyl), l-pyrrolidinyl, piperidino, morpholino or 4-methyl-1-piperazinyl; and a pharmaceutically acceptable acid addition salt thereof.

2. The compound of Claim 1: Z-amino-S-o-chlorophenyl-7-ethyl-3 H-thieno [2,3-e] 1,4] diazepine.

3. The compound of Claim 1: Z-dimethylamino-S-ochlorophenyl-7-ethyl-3 H-thieno [2,3-e] 1,4] diazepine.

4. The compound of Claim 1: Z-methylamino-S-o-chlorophenyl-7-ethyl-3H-thieno [2,3-e] 1,4] diazepine.

5. The compound of Claim 1: 2-piperidino-5-o-chlorophenyl-7-ethy1-3H-thieno [2,3-e] 1,4] diazepine.

/CH| R N=C\ /R' Example No. R It N(R=) (R) X Melting Point C.)

5 H Ethyl-.. Ethylamlno Basez188-190: l t 1 1 H MethyL--. Methylamino--.-- Base: 241-243. on a 86- 87 7 Methy Base: 275-278. R H Base: 243-245. Base: 174-176. Base: -168 Base: 141443 --.-do Base: 140442 -(CH 0 Base: 211-213.

. Ethy1.. 4-methyl-1-plperazinyL o Dimaleate: 156-158.

-...do Morpholino Dihydrochlorlde: 167-170. --.-d0-..--- Methylemino fln do dodo- Decomposition.-

Although the present invention has been adequately discussed in the foregoing specification and examples included therein, one readily recognizes that various changes and modifications may be made without departing from the spirit and scope thereof.

6. The compound of Claim 1: 2-ethylamino-5-o-chlorophenyl-7-ethyl-3H-thieno [2,3-e] [1,4] diazepine.

7. The compound of Claim 1: 2-methylamino-5-o-chlorophenyl-7-methyl-3H-thieno [2,3-e] 1,4] diazepine. 5 8. The compound of Claim 1: Z-methylamino-S-phenyl- 6,7-dimethyl-3H-thieno[2,3-e] [1,4]diazepine.

9. The compound of Claim 1: Z-methylamino-S-phenyl- 7-ethyl-3H-thieno[2 ,3-e] [1,41diazepine, v

10. The compound of Claim 1: .2-propylamino-5-ochlorophenyl-7-ethyl-3H-thieno [2,3-e] 1,4] diazepine.

11. The compound of Claim 1: Z-butylamino-S-o-chloropheny1-7-ethyl-3 H-thieno[2,3-c] 1,4] diazepine.

12. The compound of Claim 1: 2-dimethylamino-5- pheny1-7-ethyl-3 I-I-thieno[2,3-e] [1,4]diazepine.

13. The compound of Claim 1: 2-( l-pyfrolidinyD-S-ochlorophenyl-7-cthyl-3H-thieno [2,3-e] 1,4] diazepine.

14. The compound of Claim 1: 2-(1-pyrrolidinyl) -5-ochlorophcnyl 6,7,8,9 tetrahydro 3H [l]benzothieno [2,3-e] [1,4]diazepiue.

15. The compound of Claim 1: 2- (4-mcthyl-1-piperazinyl)-5-o-chlorophenyl-7-cthyl 3H thieno [2,3-e] [1,4] diazepine.

16. The compound of Claim 1: Z-morpholino-S-o-chlorophenyl-7-ethyl-3-H-thieno 2,3-e] 1,4]diazepine.

8 References Cited UNITED STATES PATENTS 3,669,959 6/1972 Hromatka et a1. 260-4393 3,558,606 1/1971 Tinney 260239.3 3,121,075 2/ 1964 Keller et a1. 260239 3,120,521 2/ 1964 Sternbach et a1 260-244 3,678,036 7/1972 Archer et a1. 260239 FOREIGN PATENTS 1,225,677 3/1971 Great Britain 260-239 HENRY JILES, Primary Examiner C. M. S. JAISLE, Assistant Examiner US. Cl. X.R.

260268 BC, 293.57, 326.55 A, 326.81, 329 F, 332.3 P, 332.5; 424-248, 250, 267, 274, 275 

